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CD83 orchestrates immunity toward self and non-self in dendritic cells
Andreas B. Wild, … , Elisabeth Zinser, Alexander Steinkasserer
Andreas B. Wild, … , Elisabeth Zinser, Alexander Steinkasserer
Published September 17, 2019
Citation Information: JCI Insight. 2019;4(20):e126246. https://doi.org/10.1172/jci.insight.126246.
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Research Article Inflammation

CD83 orchestrates immunity toward self and non-self in dendritic cells

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Abstract

Dendritic cells (DCs) are crucial to balance protective immunity and autoimmune inflammatory processes. Expression of CD83 is a well-established marker for mature DCs, although its physiological role is still not completely understood. Using a DC-specific CD83–conditional KO (CD83ΔDC) mouse, we provide new insights into the function of CD83 within this cell type. Interestingly, CD83-deficient DCs produced drastically increased IL-2 levels and displayed higher expression of the costimulatory molecules CD25 and OX40L, which causes superior induction of antigen-specific T cell responses and compromises Treg suppressive functions. This also directly translates into accelerated immune responses in vivo. Upon Salmonella typhimurium and Listeria monocytogenes infection, CD83ΔDC mice cleared both pathogens more efficiently, and CD83-deficient DCs expressed increased IL-12 levels after bacterial encounter. Using the experimental autoimmune encephalomyelitis model, autoimmune inflammation was dramatically aggravated in CD83ΔDC mice while resolution of inflammation was strongly reduced. This phenotype was associated with increased cell influx into the CNS accompanied by elevated Th17 cell numbers. Concomitantly, CD83ΔDC mice had reduced Treg numbers in peripheral lymphoid organs. In summary, we show that CD83 ablation on DCs results in enhanced immune responses by dysregulating tolerance mechanisms and thereby impairing resolution of inflammation, which also demonstrates high clinical relevance.

Authors

Andreas B. Wild, Lena Krzyzak, Katrin Peckert, Lena Stich, Christine Kuhnt, Alina Butterhof, Christine Seitz, Jochen Mattner, Niklas Grüner, Maximilian Gänsbauer, Martin Purtak, Didier Soulat, Thomas H. Winkler, Lars Nitschke, Elisabeth Zinser, Alexander Steinkasserer

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Figure 1

Successful deletion of CD83 on DCs.

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Successful deletion of CD83 on DCs.
(A) Strategy used to generate DC-spe...
(A) Strategy used to generate DC-specific deletion of CD83 (CD83ΔDC). Mating of CD83fl/fl mice with Itgax-Cre mice led to deletion of loxP-flanked exons 1 and 2, resulting in ablation of CD83 expression, specifically in CD11c+ DCs. (B) Assessment of KO efficiency on an mRNA level. BMDCs were matured with 0.1 μg/mL LPS for 16 hours, and expression levels of Cd83 were determined via quantitative PCR (qPCR). Expression levels were normalized to CD83fl/fl BMDCs. (C) Assessment of knockout efficiency on a protein level. BMDCs were stimulated with 0.1 μg/mL LPS for 16 hours or left untreated, and CD83 expression was analyzed via Western blot of whole-cell lysates. GAPDH was used as a loading control. See full, uncut gels in online supplemental material. (D) Flow cytometric evaluation of CD83 deletion on splenic DC subsets. Total splenocytes were analyzed either ex vivo or after stimulation with 3.5 μg/mL CpG ODN2395 and 1 μg/mL Pam3CSK4 (TLR ligands, TLR-Ls) for 16 hours via flow cytometry. FACS data are representative of 5 mice. (E) Assessment of MHC-II surface expression on cDCs on splenic DC subsets. Data represent 4 independent experiments (n = 16). Data are represented as mean ± SEM. Statistical analysis was performed using Mann-Whitney U test. *P < 0.05; ***P < 0.001; ns, not significant. iDC, immature DC; mDC, mature DC.

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